Ebola (EboV) and Marburg viruses are members of the Filoviridae family of enveloped viruses with nonsegmented negative-sense RNA genomes (Geisbert, et al., Nat. Med. 10, S110 (2004)). EboV Marburg virus infections are initiated by fusion between viral and host cell membranes, which is mediated by the viral membrane glycoprotein, GP (Wool-Lewis, et al., J. Virol. 72, 3155 (1998); and Takada et al., Proc. Natl. Acad. Sci. USA 94, 14764 (1997)). Mature GP is a trimer of three disulfide-linked GP1-GP2 heterodimers generated by proteolytic cleavage of the GP0 precursor polypeptide during virus assembly (Volchkov, Curr. Top. Microbiol. Immunol. 235, 35 (1999); Sanchez et al., J. Virol. 72, 6442 (1998); and Jeffers, et al., J. Virol. 76, 12463 (2002)). The membrane-distal subunit, GP1, mediates viral adhesion to host cells and is proposed to regulate the transmembrane subunit GP2, which carries out membrane fusion (Weissenhorn, et al., Mol. Cell 2, 605 (1998); Ito, et al., J. Virol. 73, 8907 (1999); and Simmons et al., Virology 305, 115 (2003)). The processing and function of EboV and Marburg GP are analogous to those of other “type I” envelope glycoproteins, such as human immunodeficiency virus (HIV) Env and influenza virus HA (Volchkov, Curr. Top. Microbiol. Immunol. 235, 35 (1999); Weissenhorn, et al., Mol Cell 2, 605 (1998); Skehel, et al., Annu. Rev. Biochem. 69, 531 (2000); Earp, et al., Curr. Top. Microbiol. Immunol. 285, 25 (2005); and Malashkevich et al., Proc. Natl. Acad. Sci. USA 96, 2662 (1999)). Based on current models of infection by these viruses (Earp, et al., Curr. Top. Microbiol. Immunol. 28525 (2005)), a specific signal within susceptible cells, such as receptor binding or exposure to acidic pH, triggers destabilization of inter-subunit contacts, conformational rearrangement of the transmembrane subunits, and membrane fusion. EboV/Marburg GP1 is believed to function as a clamp that prevents premature deployment of the GP2 membrane fusion machinery and as a sensor for the triggering signal.
The triggering signal for the EboV Marburg GP1-GP2 trimer is unknown. Specifically, an essential EboV receptor analogous to CD4/CCR5 for HIV Env has not been identified (Simmons et al., J. Virol. 77, 13433 (2003)). EboVinfection is blocked by inhibitors of endosomal acidification (Wool-Lewis, et al., J. Virol. 72, 3155 (1998); and Takada et al., Proc. Natl. Acad. Sci. USA 94, 14764 (1997)), indicating that this virus uses an acid-dependent pathway to enter cells. However, acidic pH does not induce GP-dependent cell membrane fusion (Takada et al., Proc. Natl. Acad. Sci. USA 94, 14764 (1997)), as might be expected from studies of acidic pH-triggered influenza virus and retroviruses (Boulay, et al., EMBO J. 6, 2643 (1987); and Mothes, et al., Cell 103, 679 (2000)).